The use of sleep measures to compare a new 5HT1A agonist with buspirone in humans.

The partial agonist buspirone has a REM (rapid eye movement) suppressing effect on human sleep probably via a 5HT(1A) receptor in the pontine area. Eptapirone is a new 5HT(1A) agonist with a greater intrinsic effect than buspirone. The objective of this study was to examine the effects of eptapirone on sleep architecture, particularly REM sleep, in normal volunteers and compare it with buspirone and placebo. This was a randomized, double-blind placebo-controlled four-way crossover study in 12 healthy volunteers. Volunteers were screened to ensure that they had normal overnight sleep EEG (electroencephalogram) and were extensive CYP 2D6 metabolizers. Sleep was recorded on pairs of nights on four occasions, with medication being taken before the second night. Treatments were eptapirone 1.5mg at 10 AM, eptapirone 1.5mg at 11 PM, buspirone 20mg at 11 PM and placebo. Standard measures of sleep were derived and compared among the four treatments using ANOVA. REM sleep was significantly suppressed supporting the proposition that activation of post-synaptic 5HT(1A) receptors reduces REM sleep. Sleep fragmentation increased by both drugs. REM sleep suppression was significantly greater with morning eptapirone than with buspirone. Wakefulness in sleep was significantly greatest after morning eptapirone. REM sleep effects were greatest after evening eptapirone, suggesting a greater effect on central serotonin receptors than that of buspirone.

Double-blind comparative study of the action of repeated administration of milnacipran versus placebo on cognitive functions in healthy volunteers.

OBJECTIVE: The principal objective was to compare the effects of milnacipran, an antidepressant characterized by a dual-action on serotonin and noradrenaline reuptake, with placebo on memory, attention and psychomotor performance in healthy volunteers. The secondary objective was to evaluate the effects of milnacipran on mood, anxiety and vigilance in these subjects. METHODS: In a double-blind crossover randomized trial, milnacipran (50 mg b.d.) or placebo was administered during two periods of 7 days separated by a washout period of 7 days. Memory tests (recall of words, images and coloured bars), tests to evaluate attention and vigilance (squares test, critical flicker fusion test and choice reaction time test) and visual analogue scales for affect and sleep were used. RESULTS: There were no significant differences between milnacipran and placebo groups with respect to the psychomotor functions tested. No differences were observed in the Norris scales for vigilance, anxiety or satisfaction or in the sleep questionnaire (sleep latency, sleep quality and waking). CONCLUSION: Milnacipran, administered at 100 mg per day for 7 days to healthy volunteers, had no effects on cognitive functions.

A randomised, double-blind comparison of milnacipran and imipramine in the treatment of depression.

This multicentre, double-blind, randomised trial in 109 patients compared the efficacy and tolerance of the novel selective serotonin and noradrenaline reuptake inhibitor (SNRI) antidepressant milnacipran (50 mg twice daily, n=53) with the established tricyclic agent imipramine (75 mg twice daily, n=56) over a period of 6 weeks, in patients with major depression (Montgomery-Asberg depression rating score (MADRS) > or =25). Initiation of antidepressant medication was conducted during a 2-week period of hospitalisation, after a 3- to 7-day washout period. Concomitant psychiatric medication was limited to lorazepam, cyamemazine, chloral hydrate and long-term uncomplicated lithium therapy. Assessment for efficacy using the MADRS and Hamilton rating scales of depression, a visual analogue scale and global evaluation revealed both agents to be highly effective (P=0.0001) in this group of patients. Milnacipran was found to be of similar efficacy to imipramine. Tolerance, assessed by physiological and biochemical examinations with routine inventory and spontaneous report of adverse events, revealed a clear advantage for milnacipran. The incidence of anticholinergic events with milnacipran was about half that with imipramine and the overall incidence of adverse events by either reporting method was markedly lower with milnacipran than with imipramine. Furthermore, the patient drop-out rate with imipramine was double that experienced with milnacipran. Milnacipran appears to possess equal antidepressant efficacy to imipramine but with markedly superior tolerance. Therefore, milnacipran constitutes an important new treatment option in major depression.

A double-blind comparison of the efficacy and safety of milnacipran and fluoxetine in depressed inpatients.

This double-blind, randomised, multicentre study compared the antidepressant efficacy and safety of two doses of milnacipran (100 mg/day and 200 mg/day) and fluoxetine (20 mg/day) in 289 inpatients with endogenous depression. After a placebo washout period of 4-7 days, assessments were performed weekly during the first 4 weeks, and then after 6, 8 and 12 weeks, using the 17-item Hamilton Depression Rating Scale (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression (CGI). HDRS total score was reduced by a mean of 14.8 in the milnacipran 100 mg/day group, 12.9 in the milnacipran 200 mg/day group and 12.1 in the fluoxetine 20 mg/day group. MADRS total score decreased by 17.4, 15.8 and 14.6, respectively. No significant difference could be shown between the three treatment groups for either the HDRS or MADRS total scores. However, the time-by-time change showed a trend in favour of milnacipran 100 mg/day, which was found significantly superior to fluoxetine at day 28 for several converging parameters (MADRS, CGI-3). Overall, efficacy ratings for all parameters were highest for milnacipran 100 mg/day, followed by milnacipran 200 mg/day and fluoxetine 20 mg/day. Side-effect profiles were not significantly different between groups except for a significantly greater frequency of dose-related increase in heart rate > or = 100 bpm in milnacipran recipients and a significantly greater weight loss in fluoxetine recipients.

Double-blind study of the efficacy and safety of milnacipran and imipramine in elderly patients with major depressive episode.

The novel antidepressant agent milnacipran is a dual and equipotent serotonin and noradrenaline reuptake inhibitor. The aim of this double-blind study was to compare the efficacy and safety of milnacipran (50 mg twice daily) with that of imipramine (50 mg twice daily) in elderly patients with major depressive episode. A total of 219 patients were randomly assigned to 8 weeks of double-blind treatment with either milnacipran or imipramine; 72 patients withdrew from the study. At the end of treatment no significant differences were found between milnacipran and imipramine in antidepressant efficacy. A significantly greater number of side-effects, particularly anticholinergic effects, was observed in the imipramine group. Milnacipran may be preferable to imipramine in elderly depressed patients, as it provides the same antidepressant activity as imipramine with a lower incidence of side-effects, and does not impair cognitive ability.

Clinical efficacy of milnacipran: placebo-controlled trials.

The clinical efficacy of milnacipran, a selective serotonin and noradrenaline reuptake inhibitor, was reviewed on the basis of three, multicentre, placebo-controlled trials in major depression. A dose-range study showed the superiority of milnacipran at 50 or 100 mg twice a day compared with placebo whereas the effect of 25 mg twice a day was not clearly distinguished from that of placebo. This has been confirmed by other studies where the 50-mg twice-a-day regimen was shown to be significantly more efficacious than placebo on all outcome measures (Hamilton Depression Rating Scale, Montgomery-Asberg Depression Rating Scale, Clinical Global Impression). The positive results in the individual studies were supported by a meta-analysis of the data from the three studies. A subgroup analysis of hospitalized patients in the meta-analysis showed an advantage for milnacipran, suggesting that milnacipran is effective in more severe depression.

Milnacipran and selective serotonin reuptake inhibitors in major depression.

In drug development the move from tricyclic antidepressants (TCAs) to selective serotonin reuptake inhibitors (SSRIs) involved not only the loss of the direct receptor interactions responsible for the adverse side effects of TCAs, but also the ability to inhibit the reuptake of noradrenaline. Selectivity for the single neurotransmitter, serotonin, may explain why SSRIs tend to be less efficacious than the TCAs, especially in more serious forms of depression. The advent of selective serotonin and noradrenaline reuptake inhibitors (SNRIs) has tended to confirm the idea that an action on both monoamine systems is important for maximal antidepressant efficacy. This paper reviews clinical trials comparing the new SNRI milnacipran with the SSRIs fluoxetine and fluvoxamine. A meta-analysis of the principal trials shows greater response rates (the proportion of patients with a decrease in symptom scores of 50% or more) with milnacipran (50 mg twice a day) than with fluoxetine (20 mg once a day), or fluvoxamine (100 mg twice a day) (milnacipran: 64%; SSRIs: 50%). Remission rates (the proportion of patients with Hamilton Depression Rating Scores of 7 or below) were also higher with milnacipran than with SSRIs (39 versus 28%). In one study, in which 100 mg milnacipran was given once a day in the evening, the higher response rate obtained with fluoxetine appears to be largely attributable to an inappropriate milnacipran dosage regimen. Data from a pharmacovigilance database including all patients participating in clinical trials with milnacipran (n = 5732) showed that, compared with the SSRIs, milnacipran produced fewer gastrointestinal side effects, such as nausea, and less anxiety. Milnacipran was, however, associated with a higher incidence of headache, dry mouth and dysuria. The results of these studies suggest that milnacipran is superior in efficacy to SSRIs and is equally well tolerated. Milnacipran, therefore, appears to offer a therapeutic advantage over the SSRIs.

Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results.

Milnacipran is a novel antidepressant agent which selectively inhibits the reuptake of serotonin and noradrenaline. Seven randomized, double-blind trials with a comparable design have compared the efficacy and tolerability of milnacipran with that of tricyclic antidepressants (TCAs) in patients with major depression. At a dose of 50 mg twice a day, milnacipran therapy is associated with a response rate (50% reduction in Hamilton Depression Rating Scale) of 64%. The rate of response to TCAs in these studies was 67%. In contrast to the TCAs, milnacipran was very well tolerated by the patients. The only adverse event that occurred more frequently in milnacipran-treated patients than in TCA-treated patients was dysuria (2.1% of patients treated with milnacipran). Milnacipran is as effective as TCAs in the treatment of patients with major depression and is better tolerated. Milnacipran's lack of effects on cardiovascular function offers improved safety in cases of overdose.

[Tolerance and pharmacologic effectiveness of antiglaucoma eyedrops]. / Verträglichkeit und pharmakologische Wirksamkeit von antiglaukomatösen Augentropfen.

The beta-blocking agent carteolol hydrochloride differs slightly from other beta-blockers by its intrinsic sympathomimetic activity. Its effect on intraocular pressure and heart rate was tested in a comparison with timolol maleate, as was subjective tolerance of it, in 28 eyes (14 subjects) with either ocular hypertension or simple chronic open-angle glaucoma. The two drugs had a similar effect on intraocular pressure; both were well tolerated subjectively. Carteolol lowered heart rate more in patients with higher heart rates, while timolol lowered it more in patients with lower heart rates.

[Superficial herpes simplex keratitis. Double-blind comparative trial of acyclovir and idoxuridine (author's transl)]. / Kératite herpétique superficielle. Traitement comparatif en double insu par acycloriv et idoxuridine.

In a double-blind, randomized trial 52 patients with superficial herpes simplex keratitis were treated with a new antiviral compound, acylclovir (ACV) 3% ointment, or with idoxuridine (IDU) 0.5% ointment. No statistically significant difference was found in the number of patients cured with either drug, but healing was achieved more rapidly with ACV than with IDU.

Evaluation of myocardial metabolism after prolonged circulatory arrest and under profound hypothermia. An experimental study in young dogs.

15 young dogs between the ages of 2 and 4 months and weighing less than 6 kg underwent circulatory arrest for 1 h combined with profound hypothermia and extracorporeal circulation. During reperfusion, myocardial metabolism was studied by comparing the oxygen arteriovenous content difference and lactate balance at different temperatures. As the myocardial temperatures rose, the oxygen arterial venous difference increased from 4 vol/100 ml at 25 degrees C to 10 vol/100 ml; lactate balance changed from -19.3 to +8% which because of a large rise in arterial lactate indicates a considerable increase in lactate consumption. This study shows that profound and generalized hypothermia ensures good myocardial protection during at least 1 h of ishcemia and confirms results obtained with other forms of cardiac hypothermia.

[Prevention and treatment of urinary infection in patients with an indwelling catheter: continuous vesical irrigation with a mixed antibiotic solution of neomycin and polymyxin B]. / Prévention et traitement de l'infection urinaire chez les malades porteurs d'une sonde a demeure: irrigation vésicale continue par une solution antibiotique mixte de néomycine et de polymyxine B.

A method of continuous lavage of the bladder using a solution containing a mixture of Neomycine and Polymyxine-B was tried out in 32 patients with indwelling urinary catheters. To do this, a three-channel catheter was used, lubricated with an antibacterial cream and connected to a plastic container which could be emptied without removing the catheter. This method of treatment, which was effective, well tolerated and simple to use, would appear to be a useful addition to the prevention and treatment of urinary infections in patients with in-dwelling catheters.